Gene pathway may be key to insulin resistance

One of the most reliable indicators to predict that a person will develop type 2 diabetes is the presence of insulin resistance. Insulin resistance is characterised by the lack of tissue response to insulin and is counteracted by a greater production of insulin by the pancreas. When the pancreas does not have the capacity to produce the amount of insulin required for tissues to receive glucose, glucose in the blood increases to pathological levels and the individual goes from being insulin-resistant to suffering type 2 diabetes. Although it is unclear what makes people develop insulin resistance, several studies report that resistant subjects show functional alterations in mitochondria. These intracellular organelles are responsible for transforming glucose into energy that the cell will then use to perform several functions.

A study performed by researcher Marc Liesa, a member of Antoni Zorzano’s lab at the Institute for Research in Biomedicine (IRB Barcelona), describes a new control pathway of a gene responsible for mitochrondrial fusion, a process that contributes to the correct function of these organelles. This pathway could therefore be a key component in the development of insulin resistance.

Previous studies demonstrated that people resistant to insulin have altered mitochondrial capacity to “generate” energy through a process called oxidative phosphorylation. In a study performed in 2003, two possible main actors were identified, the genes PGC1-beta and PGC1-alpha. These two genes are responsible for regulating the whole cascade of genes and proteins that allow mitochondria to produce energy by means of oxidative phosphorylation. Now, for the first time, a study has shown that another gene, called Mitofusin 2 (Mfn2), which is decreased in diabetic patients, is also controlled by PGC1- beta. This information is highly relevant because until now it was considered that PGC1-beta controlled the production of energy only by regulating the expression of mitochondrial genes responsible for oxidative phosphorylation.

One of the hypotheses is that mitochondrial fusion is crucial for the correct function of these organelles and when the gene that regulates this fusion is decreased, the function of mitochondria is also impaired. The researchers have obtained the first data that support the notion that Mfn2 plays a key role.

● The results of this study have been published in PloS One.

The role of DNA-based preventive medicine

American College of Preventive Medicine (ACPM) and Navigenics, is developing a medical education programme designed to improve physicians' understanding of genetic risk factors for disease, the current evidence about the use of genomic tools and technologies to determine risk, and promising practices for utilising those tools to aid in disease prevention. Through an unrestricted educational grant from Navigenics, ACPM is independently developing this continuing medical education (CME) course, titled Genetic Risk, Screening and Intervention, to address the growing use of genetic testing services and to examine their evidence-based impact on the practice of medicine.

“We are beginning to see healthcare’s evolvement from a discipline focused primarily on treating existing diseases and conditions to one that gives equal credence to preventing those diseases in the first place,” said ACPM Executive Director Michael Barry, CAE. “We are excited to be helping physicians on the frontline of care become more familiar with multiple risk assessment strategies and the evidence behind new technologies – including genomic applications – that can help patients better understand their risk for disease and take appropriate actions to mitigate that risk.”

ACPM members and experts in genomics, prevention and epidemiology are designing this course to delve into many issues related to genetic risk factors, screening and disease prevention. Specifically the programme: – Compares and contrasts the evidence for genetic screening and risk factors to epidemiological approaches typically used to identify disease risk; – Explores the potential benefits and harms derived from different types of genetic tests; and – Examines the current evidence around genomic association studies and provides a framework for evaluating their quality. The course will be available on the ACPM website and DVD-ROM in early 2009 and meets the standards of the Accreditation Council for Continuing Medical Education. ● For more information visit:

Genetic blueprint revealed for kidney design and formation

Researchers have generated the first comprehensive genetic blueprint of a forming mammalian organ, shedding light on the genetic and molecular dynamics of kidney development.

Part of an international consortium sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a research team led by Cincinnati Children’s Hospital Medical Center reports the creation of a detailed genome-based atlas for understanding healthy and abnormal kidney development and disease. The research provides a molecular genetic map detailing “gene expression analysis of all the major elements of kidney formation,” according to the investigators.

The study, involving embryonic mice, shows how the entire genome is regulated to produce thousands of specific genes that are mixed and re-mixed to form genetic teams. The teams work together to direct formation of 15 embryonic compartments in the developing kidney – from the earliest phases when stem cells are told how to differentiate into specific kidney cells to the development of nephrons, the kidney’s primary functioning unit.

“Given the mouse’s genetic similarities with people, this should help us understand the underpinnings of human disease,” said Steven Potter, PhD, a researcher in the division of Developmental Biology at Cincinnati Children’s and the study’s senior author.

The researchers conducted their multi-step analysis of mouse embryonic kidneys that were aged 15.5 days. This developmental time point in a mouse’s normal 19- to 21-day gestation allows multiple stages of kidney formation to be studied at once because of how the organ develops. The organ’s outer layers contain early stem cells that are still differentiating to become specific cell types, while inside the organ structures are forming at intermediate and more mature stages. This enabled measurement of varied gene expression stage-by-stage, the researchers said.

One of the study’s more unexpected discoveries is overlapping gene expression between the kidney’s different structures, according to Eric Brunskill, PhD, the study's lead author. Most of the thousands of genes involved in making a mammalian kidney are expressed at some level in every compartment. Previously it had been thought that each kidney compartment would have unique genes driving its development, and those genes would not be expressed in the cells of other structures. This is not the case, as the research team found only a small number of genes expressed exclusively in specific kidney structures.

Given that about one in every 500 births results in a kidney development abnormality, this provides insight into genetic programs that are critical to deciding how kidney stem cells form structures in the adult kidney. The researchers identified genes that regulate DNA transcription, establish functioning developmental processes, and are involved in pattern specification, cell differentiation and organ compartment shaping.

Published in the 11 November 2008 issue of Developmental Cell.

First genome sequence of cancer patient

For the first time, scientists have decoded the complete DNA of a cancer patient and traced her disease – acute myelogenous leukaemia (AML) – to its genetic roots. A large research team at the Genome Sequencing Center and the Siteman Cancer Center at Washington University School of Medicine in St. Louis sequenced the genome of the patient – a woman in her 50s who ultimately died of her disease – and the genome of her leukaemia cells, to identify genetic changes unique to her cancer.

“A genome-wide understanding of cancer is the foundation for developing more effective ways to diagnose and treat cancer,” says senior author Richard K. Wilson, PhD, director of Washington University’s Genome Sequencing Center.

The researchers discovered just 10 genetic mutations in the patient's tumour DNA that appeared to be relevant to her disease; eight of the mutations were rare and occurred in genes that had never been linked to AML. They also showed that virtually every cell in the tumour sample had nine of the mutations, and that the single genetic alteration that occurred less frequently was likely the last to be acquired.

Like most cancers, AML arises from mutations that accumulate in people’s DNA over the course of their lives. However, little is known about the precise nature of those changes and how they disrupt biological pathways to cause the uncontrolled cell growth that is the hallmark of cancer.

The researchers sequenced the patient’s full genome using genetic material obtained from a skin sample. This gave the scientists a reference DNA sequence to which they could compare genetic alterations in the patient’s tumour cells, taken from a bone marrow sample that was comprised only of tumour cells. Both samples were obtained before the patient received cancer treatment, which can further damage DNA.

Using software and analytical tools, they identified the 10 mutations (including the two previously known genetic mutations that are common to her leukaemia subtype but do not directly cause the disease). Of the eight novel mutations discovered, three were found in genes that normally act to suppress tumour growth.

Four other mutated genes appear to be involved in molecular pathways that promote cancer growth. In particular, one mutation was found in a gene family that also is expressed in embryonic stem cells and may be involved with cell self-renewal. Interestingly, the researchers note, selfrenewal is thought to be an essential feature of leukaemia cells.

Another gene alteration appears to affect the transport of drugs into the cell, and may have contributed to the patient's chemotherapy resistance.

Based on their current understanding of cancer, the researchers suspect that the mutations occurred sequentially. The first mutation gave the cell a slight tendency toward cancer, and then one by one, the other genetic alterations were acquired, with each contributing something to the cancer.

● The study is reported in the 6 November 2008 issue of the journal Nature.

How do individuals react to metabolic stress?

Metabolic diseases – particularly the increasingly prevalent type-2 diabetes – are caused by a complex interaction between genetic disposition and unfavourable lifestyle.

Researchers at the Helmholtz Zentrum München have now for the first time been able to show a relationship between the genetic make-up of an individual and differences in his/her metabolism.

The team of Professor Karsten Suhre of the Institute for Bioinformatics and Systems Biology at the Helmholtz Zentrum München and the Ludwig- Maximilians Universi-tät München (LMU) and Dr Christian Gieger and Thomas Illig of the Institute for Epidemiology in cooperation with the Innsbruck company Biocrates Life Sciences AG determined the blood test results of several hundred metabolites synchronously with more than 100,000 DNA variants of 284 adult test subjects.

By combining comprehensive genetic data with metabolite data, the scientists identified genetic variants in several genes that code for enzymes which perform important tasks in the body’s metabolism of lipids, sugars and carbohydrates. Simply expressed, the individuals in the study had different metabolic patterns (metabotypes) due to genetic factors.

While one group is able to react relatively robustly to “metabolic stress”, in the form of a short-term nutritional deficiency or a highfat diet, for instance, another group may have more or less pronounced physical impairments, the precise extent of which can now be ascertained in follow-up studies.

“For example, differences in hair colour are apparent to the observer at first glance. However, in the case of metabolism it takes much more effort to identify the role which the respective gene variant plays in the metabolism of the affected person,”

Suhre explained. In this study, by means of a genome-wide analysis, the crossinstitutional working group succeeded for the first time in profiling a number of such relationships. The identification of such genetically induced variations in the metabolism can be used in the future to predict risks with respect to certain medical phenotypes, possible reactions to medical treatment, or nutritional or environmental influences.

This is a first step towards personalised medicine and nutrition, based on a combination of a genetic and metabolic characterisation of the patients.

● Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum, PLoS Genetics, 28 November 2008.

Stem cell obstacles

“There are still a number of major hurdles in the path of stem cell research that are preventing the routine application of the technology in regenerative medicine.” So say UK scientists writing in the International Journal of Biotechnology.

In an article entitled, Blazing the trail from stem cell research to regenerative medicine, Jane Bower of the ESRC Innogen Centre, at University of Edinburgh, and colleagues highlight some of the recent advances in stem cell science.

Stem cells are immature cells that can replicate rapidly and then mature into the different cells needed around the body to build tissues in the skin, liver, heart, bone, brain, blood cells, and nerves. They are present only in limited quantities in adults but are present in huge numbers in embryonic tissue.

Human embryonic stem cells are currently the most promising source for therapeutic purposes, but their use has ethical implications. Advocates hope that this research will lead to important therapies for tackling major degenerative diseases, such as Parkinson’s, Alzheimer’s, stroke, heart disease, diabetes, cancer and arthritis.

There are also the possibilities of using stem cells to treat debilitating injuries of the spinal cord and other structural injuries. Indeed, the recent case of the trachea engineered to avoid organ rejection by using a patient's own stem cells is a prominent and early success (see page 52).

Stem cells will also have applications in discovering and testing new drugs. “Technical solutions may involve the use of human embryos and this has created barriers to the use of the technology in a number of countries,” Bower and colleagues say, “There is already a need for the progressive development of appropriate legal and regulatory frameworks to allow both the scientific and clinical research to move forward.”

The researchers explain that while there remain technical obstacles to be overcome in stem cell research, Western scientists are not the only ones working on advancing this field. Scientists in China, South Korea, and India are also taking steps forward, although revelations of scientific fraud have led to additional negative publicity.

Nevertheless, the team believes that if a high level of routine success were achieved outside the West, then this might have a positive impact on the public demand for stem cell therapies in the West and so create the political pressure necessary to address the regulatory, legal, and ethical issues sooner rather than later.

● “Blazing the trail from stem cell research to regenerative medicine” by D. Jane Bower, A. Najib Murad, Julian C. Sulej, and Joyce Tait in International Journal of Biotechnology, 2008, 10, 461-475. 

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